New Ciprofloxacin–Pyrazolopyrimidine Hybrids as Topoisomerase IV and Gyrase Inhibitors against MRSA AUMC 261

Abstract

Eleven novel ciprofloxacin–pyrazolopyrimidine hybrids 4 a–k were synthesized and structurally elucidated using NMR, elemental analysis, and mass spectrometry. The antibacterial screening showed that the newly synthesized compounds revealed a remarkable shifting of antibacterial activity from Gram–negative toward Gram–positive bacteria. Most of the synthesized hybrids displayed good to excellent activity against Staph aureus ATCC 6538 especially hybrids 4 a and 4 g which revealed MICs of 12.5 and 6.25 μg/ml, respectively, compared to the ciprofloxacin MIC, 25 μg/ml as a reference drug. In addition, both hybrids displayed potent activity toward MRSA AUMC 261 with MICs, 71 and 36 μg/ml respectively, compared to the ciprofloxacin MIC, 190 μg/ml as a reference drug. Additionally, hybrids, 4 a and 4 g exhibited effective inhibitory activity against DNA gyrase and topoisomerase IV enzymes with IC50 values, 0.404, 1.626 μM and 3.647 and 3.791 μM, respectively, compared to ciprofloxacin IC50 values 0.661 and 8.159. A molecular modeling investigation showed a high fitting affinity of hybrids 4 a and 4 g toward gyrase and topoisomerase IV active sites compared to ciprofloxacin.